SEARCH FOR ALLERGENS

Allergen Exposure

Geographical distributionCarrot is a biennial, indigenous to Europe. This member of the Parsley family has lacy green foliage and long, slender, fleshy, orange storage roots, which are eaten raw or cooked. Wild Carrots have small, woody taproots, but cultivated varieties have been improved by selection and breeding. The best Carrots are young and slender.

EnvironmentCarrot is used in a wide range of foods, including soups and stews. It is rich in sugar and has been renowned for over 2000 years for health-giving properties, and recently for high vitamin A content.

AllergensVarious allergens have been detected, including 23, 31 and 42 kDa protein bands, and 2 weaker bands between 66 and 87 kDa (1). A number of these cross-react with pollen allergens due to the presence of panallergens (2).

A 35 kDa protein related to Bet v 5, an isoflavone reductase-related protein, has been detected (23-24). Its clinical relevance was not determined.

A Bet v 6-related food allergen of approximately 30-35 kDa, which is a phenylcoumaran benzylic ether reductase (PCBER) – a plant defence protein – has been detected (4,16,25).

The presence of cross-reactive carbohydrate determinants (CCDs) has been reported (4,11,16).

Among 26 subjects with allergy to Carrot, Dau c 1 was recognised by IgE from 85%; 45% were sensitised to cross-reactive carbohydrate determinants, and 20% to Carrot profilin. In 1 subject, a Bet v 6-related Carrot allergen was recognised. In 4 patients, IgE binding to Dau c 1 was not inhibited or was only weakly inhibited by rBet v 1 or Birch pollen extract. The authors suggest that the lack of inhibition of IgE binding to Dau c 1 by Birch pollen allergens in a subgroup of patients might indicate an secondary immune response to new epitopes on the food allergen that are not cross-reactive with Bet v 1 (5).

In a study of sera from 40 Carrot-allergic patients, 98% were positive to at least 1 recombinant Carrot allergen: 98% reacted to rDau c 1.0104, 65% to rDau c 1.0201, 38% to rDau c 4 and 20% had IgE against CCD (11).

Carrot lipid transfer protein (Dau c 3), thought to be relevant in Carrot allergy, is not present at detectable levels in the edible parts of Carrot. The absence of this protein may explain why Carrot allergy is very rare in Mediterranean, countries, where LTP sensitisation is common (26).

Dau c Cyclophilin has been shown to react with about 14% of Carrot-allergic patients’ sera. No cross-reactivity between this allergen and Bet v 7, a Birch pollen cylcophilin, was observed (22).

Carrot allergens are reported to be more stable to heat and processing influences than are Apple allergens (27).

Potential cross-reactivityAn extensive cross-reactivity among the different individual species of the Apiaceae family could be expected. Members include Carrot, Celery, Fennel, Anise, Caraway, Dill, Lovage and Parsley (10,28-29). Hypersensitivity to Carrot is also frequently associated with sensitisation to Birch and Mugwort pollen (10).

In European countries, vegetables belonging to the Apiaceae family are frequent causes of pollen-related food allergy (30-32). As up to 25% of food-allergic subjects in this region are allergic to Carrot (33), it is important to evaluate Carrot-allergic patients for allergic rhinitis and/or asthma. The most frequent instances of cross-reactivity with Carrot have been reported as being to Birch pollen, Celery, a number of other vegetables, and spices (34-36).

Cross-reactivity between members of the Apiaceae family and Birch pollen is due to panallergens, in this case proteins that share common epitopes with allergens from Birch tree, i.e., Bet v 1-like proteins and profilin (4,19). Carrot contains more than 1 allergen that is cross-reactive with Birch tree pollen allergens. Approximately 70% of Europeans who are allergic to Birch pollen may experience symptoms after consumption of cross-reactive foods. The most important cross-reactive allergen is Dau c 1, cross-reactive with Bet v 1, the major Birch pollen allergen, which occurs in pollens of several tree species, and in fruits and vegetables: Apple, stone fruits, Celery, Carrot, nuts, and Soybean (37).

Cross-reactivity between Mango, Mugwort pollen, Birch pollen, Celery, and Carrot has been reported and is based on allergens related to Bet v 1 and Art v 1, the major allergens of Birch and Mugwort pollen, respectively (38).

However, sensitisation to Bet v 1 does not mean certain cross-reactivity, as indicated by a study assessing IgE binding to different food allergens in 50 Bet v 1-positive patients. It was found that 99% reacted with Mal d 1 from Apple, 93% with Cor a 1 from Hazelnut, 59% with Api g 1 from Celery and 38% with Dau c 1 from Carrot. Conversely, patients with Birch pollen-related food allergy were predominantly sensitised to Bet v 1 homologues and less frequently recognised other allergens contained in both sources, such as profilins (39).

Some individuals may have allergy to Carrot without it being associated with Birch pollen allergy (36). This observation is supported by a study of 4 patients who demonstrated strong immediate systemic reactions after contact with or ingestion of raw Carrot, all of whom had significant levels of IgE antibodies to Carrot Dau c 1; but no IgE antibodies to Birch pollen were detected in any of them. Although the Carrot IgE-binding protein’s N-terminal sequence was homologous to that of Bet v 1 and to allergens previously described in Celery and other foods, the 4 patients studied were not sensitised to Birch pollen, and 3 of them tolerated fruit ingestion. The study concluded that sensitisation to Dau c 1 induces IgE antibodies that do not cross-react with Birch pollen allergens (3). This finding is supported by a study reporting that, although cross-reactivity of the major allergens of Cherry (Pru a 1),

Minor Birch pollen allergens may also contribute to cross-reactivity: approximately 10-15% of Birch pollen-allergic individuals have IgE antibodies to a 35 kDa minor Birch pollen allergen, and cross-reactivity with proteins of comparable size from Carrot (along with Litchi, Mango, Banana, Orange, Apple, and Pear). This 35 kDa protein is immunologically independent of the major Birch pollen allergen Bet v 1 (41).

Profilin, a ubiquitous cross-reacting plant allergen related to Birch pollen Bet v 2, is also present in Carrot and may result in cross-reactivity (17-18). In an earlier study, ELISA inhibition assays demonstrated allergenic similarity among Celery, Cucumber, Carrot, and Watermelon. A 15 kDa protein band common to all 4 foods was demonstrated, and attributed to a protein now thought to be a profilin (42).

Cross-reactive patterns may vary among Birch pollen-allergic individuals and may be complex. Of 196 Birch pollen-hypersensitive patients with oral allergy syndrome (OAS), 195 had Apple and/or Hazelnut allergy, and 103 had Apiaceae sensitivity; only 1 patient had Apiaceae (Carrot, Celery, and Fennel) allergy alone. This study suggests that most Apiaceae determinants cross-react with Apple or Hazelnut determinants, whereas only some Apple or Hazelnut determinants cross-react with Apiaceae allergy determinants (43).

Carrot contains a lipid transfer protein, which may cross-react with LTP from several other plant-derived foods including Peach peel, Broccoli, Apple, Walnut, Hazelnut, Peanut, Corn, Rice and beer (14-15).

Although the cyclophilin allergen detected in about 14% of Carrot-allergic patients’ sera was found to be homologous with other plant cyclophilins, no cross-reactivity between this Carrot allergen and Bet v 7, a Birch pollen cylcophilin, was observed (22).

Some individuals may also experience cross-reactivity to Mugwort. Carrot allergy associated with a sensitisation to Celery, spices, Mugwort, and Birch pollen is often referred to as the “Celery-Mugwort-spice-syndrome” or “Celery-Carrot-Birch-Mugwort-spice syndrome” (44-48). For instance, in a study of 26 patients with histories of allergy to Carrot, 22 reported pollinosis symptoms during the Birch flowering season, and 7 reported pollinosis symptoms during the Mugwort flowering season (4).

A number of studies have reported other relationships between Carrot and other foods or pollens but have not determined the molecular reasons for these. A relationship between Birch pollen allergy and sensitisation to Carrot, Hazelnut, Apple, Potato and Kiwi has been reported (49); also reported are cross-reactions among Celery, Carrot, Parsley, and Ragweed (50); allergy to Apple, Carrot and Potato in children with Birch pollen allergy (30); cross-reactions among Kiwi, Apple, and Hazelnut; and moderate reactions to Carrot and Potato (51).

RAST inhibition experiments demonstrated that Carrot does share allergens with Lettuce, although Carrot allergens are more potent than those of Lettuce (52).

Group 4 grass pollen allergens are 60 kDa glycoproteins recognised by 70% of patients sensitive to these pollens. In Timothy grass, Mugwort, and Birch pollens, these allergens are located in the cell wall, and in Timothy grass and Birch pollens additionally in the cytoplasm. In Peanut, Apple, and Celery and Carrot root, these occurred only in the cytoplasmic areas. Group 4-related allergens thus occur in pollens of unrelated plants and plant foods and may contribute to cross-reactivity in patients allergic to various pollens and plant foods (53).

Group 4 grass pollen allergens are 60 kDa glycoproteins recognised by 70% of patients sensitive to these pollens. In Timothy grass, Mugwort, and Birch pollens, these allergens were located in the cell wall, and in Timothy grass and Birch pollens additionally in the cytoplasm. In Peanut, Apple, and Celery and Carrot root, these occurred only in the cytoplasmic areas. Group 4-related allergens thus occur in pollens of unrelated plants and in plant food and may therefore contribute to cross-reactivity in patients allergic to various pollens and plant food (42).

Carrot allergy has been reported to affect up to 25% of food-allergic subjects (33). In a Swiss study, Carrot was found to be the third-most-common food allergen, affecting 13% of food-allergic patients, and was more common than allergy to Hen’s egg or fish (63). In a similar study in Switzerland, in 173 patients with food allergy (predominantly adults), the most frequent food allergens were found to be Celery in 40.5%, Carrots (20%), Green beans (6%), eggs (21%), Milk and dairy products (20%), and fish (12%) (54). Similarly, in a German study, the most prevalent allergy was to Celery, in 44.5%, followed by Carrot (14.4%) (57). Other studies have demonstrated the high prevalence of Carrot allergy (64-65). In an Indian study of 24 children aged 3 to 15 years with documented deterioration in control of their perennial asthma, IgE antibodies to Carrot were documented in 21 (88%) (66).

The most frequently reported symptoms are oral allergy syndrome (35), but other symptoms include angioedema, urticaria, dyspnoea, vertigo, tightness of the throat or chest, dysphagia, hoarseness, conjunctivitis and rhinitis (4).

Allergy to Carrot may follow complex patterns. This is illustrated by a study that assessed the role of the Carrot allergen Dau c 1

in 3 patients with Carrot-induced asthma: Patient 1 had asthma when handling raw Carrot but was not sensitised to any pollens; Patient 2 experienced rhinoconjunctivitis due to grass, Olive pollen allergy, and asthma when handling raw Carrot; Patient 3 experienced rhinoconjunctivitis and asthma due to allergy to House dust mite, several pollens, and Cat, and asthma due to raw Carrot ingestion and inhalation. Patients 1 and 2 were shown to be sensitised to Dau c 1 from Carrot extract as well as to the recombinant rDau c 1. Bet v 1 from a Birch pollen extract was not recognised by either. Patient 3 were not sensitised to any of these allergens. Inhibition studies with Carrot showed 30% inhibition between Carrot and rDau c 1 in patient 1, nearly 100% inhibition between Carrot and rDau c 1 in patient 2, and no inhibition in patient 3. The study concluded that airborne Carrot allergens are able to sensitise without previous sensitisation to pollen. Dau c 1 was the main allergen in patient 2. In patient 1, there was a 30 kDa protein band that appeared to be the predominant allergen. Patients 1 and 2 were sensitised directly from Carrot allergens. In patient 3, Carrot allergy was not caused by Dau c 1 but seemed to be related to allergy to pollens other than Birch pollen (9).

A number of case reports further demonstrate how adverse reactions may vary among individual patients.

In a report on 2 patients with allergy to Carrot, 1 presented with sneezing, rhinorrhoea, contact urticaria on her hands and face, and coughing and wheezing after handling raw Carrots. She experienced no symptoms after eating cooked Carrots, but oropharyngeal itching, hoarseness, cough and wheezy dyspnoea occurred after eating raw Carrots. The second experienced oropharyngeal itching, a swollen throat, hoarseness and asthma after eating raw Carrots, and had similar but milder symptoms after eating cooked Carrots. She experienced itching of her hands, palpebral angioedema, ocular and nasal itching, and rhinorrhoea when handling raw Carrots. Bronchial provocation with Carrot extract elicited a FEV1 fall of 30% within 10 minutes (1).

A 34-year-old female cook experienced allergic rhinoconjunctivitis and contact urticaria with severe itching on both hands when she handled raw Carrot. The patient had had anaphylactic episodes after accidental ingestion of raw Carrots, but tolerated cooked Carrots. In this instance, monosensitisation to an 18 kDa protein in Carrot was reported (67).

Other studies have reported allergy to Carrot in adults. Two adult patients with respiratory and/or ocular symptoms from handling or eating Carrot and/or Lettuce were shown to have, on challenge, prolonged nasal obstruction and ocular symptoms (68).

A study of a 50-year-old non-pollen-allergic woman who presented with vomiting, diarrhoea, dyspnoea, and generalised urticaria to Carrot juice suggests that the allergen involved was a thermolabile, low-molecular-weight allergen, probably not related to any of the Carrot allergens identified so far (16).

A 38-year-old woman developed rhino-conjunctivitis, dyspnoea and general malaise after inhaling steam of cooking Green bean, Potato and Carrot. She reported contact dermatitis when preparing these vegetables. A bronchial provocation test with Carrot resulted in a FEV1 decrease, and in an intense cough and general malaise that lasted for more than 24 hours (12).

Although Carrot is frequently involved in food allergy and oral allergy syndrome, usually in association with other foods, it alone is rarely responsible for severe systemic reactions (69). Nevertheless, anaphylaxis has been described (70-71). As with other foods, anaphylaxis may occur to minute quantities of allergen, as described in an individual who developed anaphylactic shock due to the inadvertent ingestion of Carrot as a hidden allergen contained in ice cream (69).

Allergic manifestations in the skin have been reported. Contact urticaria to fresh Carrot has been described. A 16-year-old boy and a 45-year-old woman were reported on, the former with dermatitis and urticaria affecting the perioral area, hands and nape of the neck, and the latter with symptoms involving the face and hands. Individuals transfer the allergen to these areas through scratching or merely touching (72).

Allergic contact dermatitis from Carrot has been described. Exposure is usually occupational rather than domestic. Carrot is among the commonest causes of contact dermatitis of the hands (73-79).

A 38-year-old man experienced a single episode of facial allergic contact dermatitis, which developed after peeling and grating raw Carrots in the kitchen at home (74). In a study of 57 children under 1 year of age, 43 children aged 12 to 35 months, and 42 children aged 3 to 15 years with atopic dermatitis, they were skin-tested with foods suspected to have caused their dermatitis and other possible allergic symptoms. Hen’s egg was the most common food allergen in children under 1 year of age. After that age, Apple, Carrot, Pea, and Soybean elicited positive reactions as often as egg (73).

In a report, ingestion of 60 ml of freshly squeezed Carrot juice 2 hours after intake of 100 mg of aspirin induced striking angioedema and shortness of breath in an individual after 3 further hours, whereas a challenge with either on separate occasions did not result in any reaction (80).

Carrot has also been reported to result in eosinophilic cystitis (81).

Carrot may result in occupational allergy and is a cause of allergic dermatitis in the food industry (82). A 40-year-old female cook described sneezing, rhinorrhoea, contact urticaria and wheezing within few minutes of handling or cutting raw Carrot. Skin tests were positive to Carrot, Celery, Aniseed and Fennel. A rubbing test with fresh Carrot was positive. The level of IgE antibodies to Carrot was 4.44 kUA/l. A bronchial provocation test was positive, but instead of introducing the Carrot extract in the usual methodology, the patient was asked to peel and handle Carrot. She was shown to be sensitised to Dau c 1 and a 30 kDa Carrot protein thought possibly to correspond to a phenylcoumaran benzylic ether reductase (PCBER) (10).

In a study of the value of IgE antibody testing as compared to SPT for Carrot allergy, 20 of 26 patients were positive to Carrot in a DBPCFC study. IgE antibodies for Carrot (> 0.7 kUA/l) were demonstrated in 90%. The presence of skin reactivity tested through commercial extracts was shown in 26%, and through prick-to-prick tests with raw Carrot, in 100% (4).

Other reactionsPhytophotodermatitis is a phototoxic dermatitis resulting from contact with psoralen-containing plants such as Celery, Limes, Parsley, Figs, and Carrots (83-84).

Consuming large quantities of Carrots may result in inadvertent increased vitamin A intake, which may cause papilloedema, as described in a patient with documented idiopathic intracranial hypertension; she had consumed large quantities of raw Carrots as part of a fad diet (85). Another adverse effect of ingesting large quantities of Carrots, usually in the form of Carrot juice, is carotenaemia, also known as xanthoderma, in which the individual’s skin develops an orange colour (86). This has also been reported from the excessive consumption of Carrot products from nursing bottles in children ages 1 to 5 (87).

Carrot soup can be the cause of met-hemoglobinemia in infants (88-91). This appears to be due to the soup being rich in nitrate and nitrite (92). Fresh and canned Carrots have been reported to contain between 40 and 850 mg NO3/kg Carrot. Processed infant foods made of Carrots was found to contain between 55 and 215 mg NO3/kg (93).

Carrot has been reported to have monoamine oxidase inhibiting activity (94).

Carrot, though a common vegetable, has been involved in unusual clinical phenomena, including Carrot addiction (95). Air embolism occurred in a 40-year-old woman subsequent to vaginal insertion of a Carrot for an autoerotic purpose. The Carrot acted like a piston, displacing a sufficient amount of air to create an air embolism (96). This condition needs to be differentiated from anaphylaxis resulting from allergy to Carrot.

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